It has been proposed that sphingosine-1-phosphate [(2S,3R,4E)-2-amino-3-hydroxyoctadec-4-enyl-1-phosphate; hereinafter optionally referred to as S1P], which is a lipid synthesized through intracellular metabolic turnover of sphingolipids and with the activity of an extracellular secretory sphingosine kinase, acts as an intracellular messenger and as an intracellular second messenger.
Recently, cloning of S1P receptor has made remarkable progresses, and as a result, it has been reported that the G-protein coupled receptors of EDG-1 (S1P1), EDG-3 (S1P3), EDG-5 (AGR16/H218/S1P2), EDG-6 (S1P4) and EDG-8 (S1P5) are the specific S1P receptors.
With particular reference to EDG-5, it has been reported that the mRNA expression is strongly recognized in the tissues of the heart, lungs, stomach, and small intestine, and that in the arterial sclerosis model of coronary artery, or the mice carotid balloon injury model, the mRNA expression level in the intima cells significantly decreases as compared with the normal ones [see the specification of JP-A 6-234797].
It is also reported that the S1P receptor (especially EDG-5) is involved in the increased portal vein pressure, asthma and the like (see Biochem. Biophys. Res. Commun., 2004, 320(3), 754-759, Mol. Immunol., 2002, 38(16-18), 1239-1245 and FASEB J., 2003, 17(13), 1789-1799).
It is disclosed that the pyrazopyridine compound of the formula (a):
wherein R1a, R2a and R3a each represent C1-8 alkyl and the like; R4a represents hydrogen and the like; R5a and R6a, being the same or different, individually represent hydrogen, C1-8 alkyl, C1-6 alkoxy, halogen and the like; Xa represents —NH—, —O—, —CH2— and the like; Ya is —NH— and the like; Za represents —CO— and the like; Wa represents —NH— and the like; ring Aa is aryl, heteroaryl and the like; (essence was quoted) or a pharmaceutically acceptable salt thereof acts on EDG-5 specifically, and is useful as a treating agent for fibrosis (see WO 01/98301 pamphlet).
And it is also disclosed that the N-containing compound of the formula (b):
wherein R1b is an optionally substituted —CnbH(2nb-2mb)CH3 or optionally substituted aryl; R2b is hydrogen, alkyl or alkylcarbonyl (essence was quoted) or a pharmaceutically acceptable salt antagonizes the EDG receptor (see WO 03/040097 pamphlet).